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WO1997019039A1 - Synthese en phase solide de composes heterocycliques et d'une banque combinatoire de composes - Google Patents

Synthese en phase solide de composes heterocycliques et d'une banque combinatoire de composes Download PDF

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Publication number
WO1997019039A1
WO1997019039A1 PCT/EP1996/004808 EP9604808W WO9719039A1 WO 1997019039 A1 WO1997019039 A1 WO 1997019039A1 EP 9604808 W EP9604808 W EP 9604808W WO 9719039 A1 WO9719039 A1 WO 9719039A1
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WO
WIPO (PCT)
Prior art keywords
solid phase
phase synthesis
synthesis according
alkyl
substituted
Prior art date
Application number
PCT/EP1996/004808
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English (en)
Inventor
Andreas Marzinzik
Eduard Felder
Original Assignee
Novartis Ag
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Novartis Ag filed Critical Novartis Ag
Priority to AU75642/96A priority Critical patent/AU7564296A/en
Publication of WO1997019039A1 publication Critical patent/WO1997019039A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C40—COMBINATORIAL TECHNOLOGY
    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B40/00—Libraries per se, e.g. arrays, mixtures
    • C40B40/04—Libraries containing only organic compounds
    • C—CHEMISTRY; METALLURGY
    • C40—COMBINATORIAL TECHNOLOGY
    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B50/00—Methods of creating libraries, e.g. combinatorial synthesis
    • C40B50/14—Solid phase synthesis, i.e. wherein one or more library building blocks are bound to a solid support during library creation; Particular methods of cleavage from the solid support

Definitions

  • reaction sequence on solid phase suitable for the generation of molecular diversity on small heterocycles of the pyrazole and isoxazole type.
  • suitable conditions on solid phase were worked out and a variety of reactive agents (building blocks) was utilized in an effort to grasp the system's breadth of applicability.
  • the inventive reaction sequence can be applied, for example, to exploit by the combinatorial approaches of the split and mix concept.
  • inventive method using the inventive method a new facile way for the synthesis of combinatorial compound libraries consisting of modified heterocyclic rings in high yields and purity is provided. These combinatorial compound libraries serve as valuable reservoirs for the screening for pharmaceutically active compounds.
  • the current invention concerns a solid phase synthesis of a heterocyclic ring, characterized in that it comprises the following steps:
  • a solid carrier having reactive surface groups is loaded directely or via a spacer group with a compound bearing an acetyl function
  • step b) optional the reaction product of step b) is modified with an ⁇ -alkylation step, and d) the heterocyclic ring is closed using a compound comprising two nucleophiles, wherein at least one of said nucleophiles is NH 2 .
  • step a) is of formula 1
  • Z is a solid carrier
  • R 1 is a substituted or unsubstituted conjugated system that has no acidic hydrogen atoms
  • R 5 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkylaryl, C 1 -C 6 alkoxy-C 1 -C 6 alkyl, C 1 -C 6 alkoxycarbonyl- C 1 -C 6 alkyl; each of which may be substituted or unsubstituted; step b) is of formula 2
  • R 1 and R 5 are defined as above;
  • R 2 is substituted or unsubstituted C 1 -C 6 alkyl, or a substituted or unsubstituted aromatic or aliphatic ring;
  • R 4 is C 1 -C 6 alkyl, preferred is methyl and ethyl; the optional step c) is of formula 3
  • R 1 , R 2 and R 4 are defined as above;
  • R 5 is hydrogen
  • X is a halogen, preferred is I, Br or Cl;
  • R 3 is C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 alkylcarbonyl-C 1 -C 6 alkylene, arylcarbonyl-C 1 - C 6 alkylene, or a substituted or unsubstituted aromatic or aliphatic ring; and step d) is of formula 4
  • Y is a nucleophilic center like NH, NC 1 -C 4 alkyl, Naryl and O; preferred are O, NH, NC 1 - C 4 alkyl, NC 1 -C 4 alkyl aryl, Naryl unsubstituted or substituted with up to four Br, Cl, I, F, C 1 - C 4 alkyl, NO 2 , SO 2 C 1 -C 4 alkyl, OC 1 -Calkyl, carboxy or carbonyl groups, suitable aryl groups are for example thienylene, thiantrenylene, furylene, phenoxanthiinylene, isobenzofuranylene, pyrazolylene, isothiazolylene, isoxazolylene, pyridinylene pyrazinylene, pyrimidylene, indolizinylene, indazolylene, isoquinolylene, quinolylene phthalazinylene, naphthyridinylene, quinoxalinylene,
  • the solid carrier Z is a resin.
  • Z is a particle that is insoluble in the reaction media and to which the ligand can be bound in sufficient amount by means of reactive groups at the surface of the this particle.
  • the binding of ligand and tag is effected, e.g. by amino, carboxyl, hydroxyl or halogen groups. These reactive groups are usually already constituents of the solid carrier, but they can also be applied or modified subsequently.
  • the solid carrier customarily employed in solid-phase synthesis can be used, for example those used in Merrifield peptide synthesis. They consist largely of a polystyrene molecule that is crosslinked by copolymerization with divinyl benzene. The molecules are additionally derivatised to attach the reactants in the solid-phase synthesis.
  • R 1 is ethinylene, thienylene, thiantrenylene, furylene, phenoxanthiinylene, isobenzofuranylene, pyrazolylene, isothiazolylene, isoxazolylene, pyridinylene, pyrazinylene, pyrimidylene, indolizinylene, indazolylene, isoquinolylene, quinolylene, phthalazinylene, naphthyridinylene, quinoxalinylene, quinazolyl
  • R 1 are benzene, , and
  • a preferred R 2 is, for example ethinyl, thienyl, thiantrenyl, furyl, phenoxanthiinyl, isobenzo- furanyl, pyrazolyl, isothiazolyl, isoxazolyl, pyridinyl, pyrazinyl, pyrimidyl, indolizinyl, indazolyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolyl, cinnolinyl, phenyl and naphthyl; wherein these conjugated systems are unsubstituted or substituted by groups that have no acidic hydrogens.
  • phenyl 4-CH 3 OC 6 H 4 , 4-ClC 6 H 3 (2CI), 4-CH 3 OOCC 6 H 4 , 4-NCC 6 H 4 , furyl, pyrrolyl, thienyl, pyridyl, methyl pyrridyl, pyrazinyl, C 6 H 5 COOCH 3 , C 6 F 5 , C 6 H 4 C(CH 3 ) 3 , C 6 H 4 OCF 3 , C 6 H 4 OCH 2 C 6 H 5 , C 6 H 4 O,(CH 2 ) 15 CH 3 , C 6 H 3 (CF 3 ) 2, C 6 H 4 O(CH 2 ) 3 CH 3 , C 6 H 4 CI, C 6 H 4 CN, naphthyl, C 6 H 4 N(CH 3 ) 2 , C 6 H 4 C 6 H 5 , C 6 H 4 OCH 3 , C 6 H 4 C 6 H 4 COOCH 3 , C 6 H 2 (OCH 3 ) 3
  • a preferred R 3 is, for example, hydrogen, C 1 -C 6 alkyl, C 1 -C 4 alkoxy-C 1 -C 4 alkyl, C 1 -C 6 alkenyl, C 1 -C 4 alkoxy-aryl, C 1 -C 5 alkanoyloxy-C 1 -C 6 alkyl, C 1 -C 6 alkoxycarbonyl-C 1 -C 5 alkyl.
  • the inventive solid phase synthesis can be used for the generation of combinatorial compound libraries, e.g., in a the split and mix concept (Furka et al., Abstr. 14th Int. Congr. Biochem., Prague (1988), 5, 47; Furka et al., Int. J. Peptide Protein Res. (1991), 37, 487).
  • the solid support is loaded with the R 1 component bearing the acetyl function (see table 1). Its carbonyl group is activated by standard methods and anchored to the acid labile Rink amide linker on polystyrene (Rink, Tetrahedron Lett. (1987), 28, 3787). We observe quantitative transformations within 1 hour, unless ortho substituted bifunctional derivatives like o-acetophenone and acetylphthalanilidic acid are used, which undergo ring closure side reactions (Nishio et al., Heterocycl. Chem. (1995), 32, 883).
  • Ring closure to form a heterocyclic scaffold is tested successfully with hydrazines 4a-d and hydroxylamine (5a) (see table 4). With the non-alkylated intermediate 2a a faster cyclization kinetics than with 3a is observed. N-mono-substituted reagents are expected to yield regioisomers with equal efficiency, unless the intermediates would bear large differences of steric and electronic properties at the R 1 and R 2 sites. During the validation process we isolate both regioisomers of model compound 4d.
  • the NH2-linker group is acylated with 0.3 M-solution of acetyl carboxylic acid (3 eq) at RT (preactivation 40 min with 3.3 eq DICD and 3.3 eq HOBt) until the Kaiser test (Kaiser et al., Anal. Biochem. (1970), 34, 595) is negative. c) Claisen condensation
  • a suitable method for the preparation of a combinatorial compound library comprises, for example, the reaction steps as described above, wherein optionally before a reaction step is carried out,
  • reaction step is carried out in each portion using a different chemical compound or reaction
  • Alos embraced by the scope of the current invention is the combinatorial compound library obtainable by the method described above.
  • a solid carrier having reactive surface groups is loaded with a compound bearing an acetyl function; or the resin is divided first into several portions then loaded with a different compound bearing an acetyl function in each portion and mixed again. Afterwards, e.g. , the pool containing the modified resin is divided into several separate portions again. The Claisen condensation is carried out in each portion using a different reagent to get different compounds.
  • HPLC analytical separation is achieved using a reverse phase nucleosil C18 5 ⁇ 250 mm ⁇ 4.6 mm column, 215 nm, 10-90% CH 3 CN / 0.1% TFA over 30 mm, 1 ml/min.
  • a part of the eluate (split 1 :25) is introduced into a Quattro-BQ mass spectrometer (VG Biotech, Altnncham, England), operating at a source temperature of 60°C and a cone voltage of 50 V, via an electrospray interface (EI).
  • EI electrospray interface
  • the modified resin of example 1 are suspended in a solution of 675 ⁇ mol carboxylic ester in 670 ⁇ l DMA (see table 5). Under inert gas 18 mg (450 ⁇ mol) of sodium hydride (60%) is added and the reaction mixture is well shaken for 1h at 90 °C. The resin is filtered, ished (30% v/v acetic acid / H 2 O, DMA, DMSO, and i-propanole), and dried under reduced pressure.
  • This modified resin is heated with 500 ⁇ l of a 2.5 M solution of a nucleophile (HCl is neutralized by N(CH 3 CH 2 ) 3 ) in DMA for 20-24 h (see table 6) to give the desired heterocyclic products (see table 6).
  • Example 6 Ring closure with compound that has a weak tendency to cyclize
  • the NH 2 -linker group of 1.50 g 4-(2',4'-Dimethoxyphenyl-fmoc-aminomethyl)phenoxy resin (Rink amide resin) is acylated with a 0.3 M-solution of a compound of formula 10 (3 eq) at RT (after preactivation for 40 mm with 3.3 eq DICD and 3.3 eq HOBt) until the Kaiser test (Kaiser, E. et al. Anal. Biochem 1970, 34, 595) is negative to form a compound of formula 11.
  • a portion of the product is cleaved from the resin as defined above and analyzed
  • a portion of the product is cleaved from the resin as defined above and analyzed.
  • the product is cleaved from the resin with 20% v/v TFA/CH 2 Cl 2 as defined above.
  • HPLC preparative separation is achieved using a reverse phase nucleosil C18 5 ⁇ 20 mm ⁇
  • acetyl carboxylic acids R a 1 to R a 4 are coupled to the resin in separate vessels.
  • the four portions are mixed and distributed in 35 vessels, where each portion reacted with a distinct R c reagent, a carboxylic acid ester.
  • the result is a randomized R a and a fixed R c position.
  • the beads are mixed again and divided into 42 equal portions, of which 41 are reacted with monosubstituted hydrazines R e .
  • the remaining last portion of the beads is reacted with hydroxylamme to an isoxazole library comprising 280 compounds.
  • the reagents are used are defined below.
  • Cyclization 1.6 g (640 ⁇ mol) are separated in 42 reaction vessels and each resin is treated with 790 ⁇ l of a 0.5 M solution of the appropriate monosubstituted hydrazine in DMA (agent for R e ). After heating the reaction mixtures for 3 days at 90°C each portion is washed separately with DMA, DMSO , and i-PrOH.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Engineering & Computer Science (AREA)
  • Structural Engineering (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Dans cette invention, on fait état d'une étude sur la séquence de réactions en phase solide, appropriée à la formation d'une diversité moléculaire sur des hétérocycles courts du type pyrazole et isoxazole. Pour chaque réaction, on a mis au point des conditions appropriées en phase solide, et on a utilisé plusieurs agents réactifs (éléments structuraux) dans le but d'appréhender l'étendue de l'applicabilité du système. On peut appliquer la séquence de réactions de l'invention, par exemple, pour exploiter des approches combinatoires du concept 'scinder et mélanger'.
PCT/EP1996/004808 1995-11-17 1996-11-05 Synthese en phase solide de composes heterocycliques et d'une banque combinatoire de composes WO1997019039A1 (fr)

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AU75642/96A AU7564296A (en) 1995-11-17 1996-11-05 Solid phase synthesis of heterocyclic compounds and combinatorial compound library

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EP95810717 1995-11-17
EP95810717.9 1995-11-17

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WO1997019039A1 true WO1997019039A1 (fr) 1997-05-29

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Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999037630A1 (fr) * 1998-01-23 1999-07-29 Versicor, Inc. Banques combinatoires d'oxazolidinones, compositions a base de tels composes et procedes de preparation
WO2000046206A1 (fr) * 1999-02-04 2000-08-10 Bayer Aktiengesellschaft Derives de pyrazolbenzylamine substitues utilises pour combattre les anemies
WO2000046208A1 (fr) * 1999-02-04 2000-08-10 Bayer Aktiengesellschaft Acides pyrazolcarboxyliques substitues utilises pour combattre les anemies
WO2000045894A3 (fr) * 1999-02-04 2001-04-19 Bayer Ag Utilisation d'amides d'acides pyrazol-carboxyliques
WO2001049681A1 (fr) * 1999-12-30 2001-07-12 H. Lundbeck A/S Procede de preparation de derives de benzene substitue
WO2000045799A3 (fr) * 1999-02-04 2002-01-24 Bayer Ag Utilisation d'acides isoxazolcarboxyliques substitues et de leurs derives, et nouvelles substances
US6562844B2 (en) 1998-01-23 2003-05-13 Pharmacia & Upjohn Company Oxazolidinone combinatorial libraries, compositions and methods of preparation
US7002020B1 (en) 1998-01-23 2006-02-21 Pharmacia & Upjohn Company Oxazolidinone combinatorial libraries, compositions and methods of preparation
WO2006021277A1 (fr) 2004-08-21 2006-03-02 Merck Patent Gmbh Monomeres, oliogomeres et polymeres de thieno[2,3-b]thiophene
KR100790916B1 (ko) 1999-12-30 2008-01-03 하. 룬트벡 아크티에 셀스카브 치환 페닐-피페라진 유도체, 그들의 제조 및 사용
CN101062916B (zh) * 2006-04-29 2012-12-26 中国人民解放军军事医学科学院毒物药物研究所 三取代1h-吡唑化合物、其制备方法、药物组合物及其制药用途
US8932992B2 (en) 2001-06-20 2015-01-13 Nuevolution A/S Templated molecules and methods for using such molecules
US9096951B2 (en) 2003-02-21 2015-08-04 Nuevolution A/S Method for producing second-generation library
US9109248B2 (en) 2002-10-30 2015-08-18 Nuevolution A/S Method for the synthesis of a bifunctional complex
US9121110B2 (en) 2002-12-19 2015-09-01 Nuevolution A/S Quasirandom structure and function guided synthesis methods
US9574189B2 (en) 2005-12-01 2017-02-21 Nuevolution A/S Enzymatic encoding methods for efficient synthesis of large libraries
US10730906B2 (en) 2002-08-01 2020-08-04 Nuevolutions A/S Multi-step synthesis of templated molecules
US10731151B2 (en) 2002-03-15 2020-08-04 Nuevolution A/S Method for synthesising templated molecules
US11118215B2 (en) 2003-09-18 2021-09-14 Nuevolution A/S Method for obtaining structural information concerning an encoded molecule and method for selecting compounds
US11225655B2 (en) 2010-04-16 2022-01-18 Nuevolution A/S Bi-functional complexes and methods for making and using such complexes

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3948937A (en) * 1972-02-29 1976-04-06 E. I. Du Pont De Nemours And Company Pyrazole plant growth regulants
US5288514A (en) * 1992-09-14 1994-02-22 The Regents Of The University Of California Solid phase and combinatorial synthesis of benzodiazepine compounds on a solid support

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3948937A (en) * 1972-02-29 1976-04-06 E. I. Du Pont De Nemours And Company Pyrazole plant growth regulants
US5288514A (en) * 1992-09-14 1994-02-22 The Regents Of The University Of California Solid phase and combinatorial synthesis of benzodiazepine compounds on a solid support

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
A.L. MARZINZIK ET AL.: "Solid Support Synthesis of Highly Functionalized Pyrazoles and Isoxazoles; Scaffolds for Molecular Diversity", TETRAHEDRON LETTERS, vol. 37, no. 7, 12 February 1996 (1996-02-12), OXFORD GB, pages 1003 - 1006, XP002025142 *
L.F. TIETZE ET AL.: "A General and Expedient Method for the Solid-Phase Synthesis of Structurally Diverse 1-Phenylpyrazolone Derivatives.", SYNLETT, no. 7, July 1996 (1996-07-01), STUTTGART DE, pages 667 - 668, XP002025143 *
N.K. TERRETT ET AL.: "Combinatorial Synthesis - The Design of Compound Libraries and their Application to Drug Discovery", TETRAHEDRON, (INCL TETRAHEDRON REPORTS), vol. 51, no. 30, 24 July 1995 (1995-07-24), OXFORD GB, pages 8135 - 8173, XP002025141 *
S. HOBBS DEWITT ET AL.: ""Diversomers": An approach to nonpeptide, nonoligomeric chemical diversity", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF USA, vol. 90, no. 15, 1 August 1993 (1993-08-01), WASHINGTON US, pages 6909 - 6913, XP002025140 *

Cited By (30)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6531470B1 (en) 1998-01-23 2003-03-11 Pharmacia & Upjohn Company Oxazolidinone combinatorial libraries, compositions and methods of preparation
WO1999037630A1 (fr) * 1998-01-23 1999-07-29 Versicor, Inc. Banques combinatoires d'oxazolidinones, compositions a base de tels composes et procedes de preparation
US7002020B1 (en) 1998-01-23 2006-02-21 Pharmacia & Upjohn Company Oxazolidinone combinatorial libraries, compositions and methods of preparation
US6562844B2 (en) 1998-01-23 2003-05-13 Pharmacia & Upjohn Company Oxazolidinone combinatorial libraries, compositions and methods of preparation
US6239152B1 (en) 1998-01-23 2001-05-29 Pharmacia & Upjohn Company Oxazolidinone combinatorial libraries, compositions and methods of preparation
WO2000045894A3 (fr) * 1999-02-04 2001-04-19 Bayer Ag Utilisation d'amides d'acides pyrazol-carboxyliques
WO2000045799A3 (fr) * 1999-02-04 2002-01-24 Bayer Ag Utilisation d'acides isoxazolcarboxyliques substitues et de leurs derives, et nouvelles substances
WO2000046208A1 (fr) * 1999-02-04 2000-08-10 Bayer Aktiengesellschaft Acides pyrazolcarboxyliques substitues utilises pour combattre les anemies
WO2000046206A1 (fr) * 1999-02-04 2000-08-10 Bayer Aktiengesellschaft Derives de pyrazolbenzylamine substitues utilises pour combattre les anemies
WO2001049681A1 (fr) * 1999-12-30 2001-07-12 H. Lundbeck A/S Procede de preparation de derives de benzene substitue
KR100790916B1 (ko) 1999-12-30 2008-01-03 하. 룬트벡 아크티에 셀스카브 치환 페닐-피페라진 유도체, 그들의 제조 및 사용
US8932992B2 (en) 2001-06-20 2015-01-13 Nuevolution A/S Templated molecules and methods for using such molecules
US10669538B2 (en) 2001-06-20 2020-06-02 Nuevolution A/S Templated molecules and methods for using such molecules
US10731151B2 (en) 2002-03-15 2020-08-04 Nuevolution A/S Method for synthesising templated molecules
US10730906B2 (en) 2002-08-01 2020-08-04 Nuevolutions A/S Multi-step synthesis of templated molecules
US10077440B2 (en) 2002-10-30 2018-09-18 Nuevolution A/S Method for the synthesis of a bifunctional complex
US11001835B2 (en) 2002-10-30 2021-05-11 Nuevolution A/S Method for the synthesis of a bifunctional complex
US9109248B2 (en) 2002-10-30 2015-08-18 Nuevolution A/S Method for the synthesis of a bifunctional complex
US9284600B2 (en) 2002-10-30 2016-03-15 Neuvolution A/S Method for the synthesis of a bifunctional complex
US9121110B2 (en) 2002-12-19 2015-09-01 Nuevolution A/S Quasirandom structure and function guided synthesis methods
US9096951B2 (en) 2003-02-21 2015-08-04 Nuevolution A/S Method for producing second-generation library
US11118215B2 (en) 2003-09-18 2021-09-14 Nuevolution A/S Method for obtaining structural information concerning an encoded molecule and method for selecting compounds
US11965209B2 (en) 2003-09-18 2024-04-23 Nuevolution A/S Method for obtaining structural information concerning an encoded molecule and method for selecting compounds
TWI393728B (zh) * 2004-08-21 2013-04-21 Merck Patent Gmbh 噻吩并〔２，３-ｂ〕噻吩之單體、寡聚物和聚合物
US8114316B2 (en) 2004-08-21 2012-02-14 Merck Patent Gmbh Monomers, oligomers and polymers of thieno[2,3-b]thiophene
WO2006021277A1 (fr) 2004-08-21 2006-03-02 Merck Patent Gmbh Monomeres, oliogomeres et polymeres de thieno[2,3-b]thiophene
US9574189B2 (en) 2005-12-01 2017-02-21 Nuevolution A/S Enzymatic encoding methods for efficient synthesis of large libraries
US11702652B2 (en) 2005-12-01 2023-07-18 Nuevolution A/S Enzymatic encoding methods for efficient synthesis of large libraries
CN101062916B (zh) * 2006-04-29 2012-12-26 中国人民解放军军事医学科学院毒物药物研究所 三取代1h-吡唑化合物、其制备方法、药物组合物及其制药用途
US11225655B2 (en) 2010-04-16 2022-01-18 Nuevolution A/S Bi-functional complexes and methods for making and using such complexes

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